Derivatives methylisoxazole, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention provides new derivatives of methylanisole formula (I)

,

in which R represents a group

,

in which R4represents hydrogen, hydroxy-, (C1-C6)-alkoxy, (C2-C6)-alkanoyloxy-, carboxy-, nitro-group, or group with other7in which R7represents hydrogen or (C1-C6)-alkyl,

R5represents hydrogen, (C1-C6)-alkyl or halogen, and

R6is hydrogen or (C1-C6)-alkyl, equal to zero, 1 or 2,

R1is hydrogen, (C1-C6)-alkyl or (C2-C6-alkanoyl,

R2represents hydrogen, (C1-C6)-alkyl, halogen, cyano, carboxyl, nitro group, or the group-other7in which R7is set higher than the value

R3is hydrogen, (C1-C6)-alkyl or (C2-C6-alkanoyl, and their pharmaceutically acceptable salts, and in which, when both R2is hydrogen, (C1-C6)-alkyl, halogen or cyano and R3represents hydrogen, R1and have installed hydrogen, and which are used as tyrosine kinase inhibitors.

The invention relates to new derivatives of 3-methylene-2-oxindole, method of production thereof, to pharmaceutical compositions containing these compounds and to their use as therapeutic agents.

From the prior art known to some methylene-oxindole derivatives. For example, in WO-A-91/13055 describes derivatives of methylene-oxindole inhibiting tyrosinekinase. In JP-A-3213847 described using methylisoquinoline derivatives as materials for pictures, while there is no indication that they have biological activity. In the publication ['an. J. Chem. Vol. 46, No. 13, page 2189-2198 (1968) reported on the testing of derivatives of methylene-oxindole against the growth of Bacillus subtilis, and publication Chem. Ber. Vol. 102 (4), 1347-1356 (1969) describes the synthesis of some oxindol derivatives of 2 - and 3-indole, however, revealed no biological activity, which would have these connections.

The invention is compounds having the following General formula (I)

< / BR>
where R represents a group

< / BR>
in which

R4represents hydrogen, hydroxy, (C1-C6)-alkoxy-(Sodom or (C1-C6)-alkyl;

R5represents hydrogen, (C1-C6)-alkyl or halogen; and

R6represents hydrogen or (C1WITH6)alkyl;

n is zero, 1 or 2;

R1represents hydrogen, (C1-C6)-alkyl, or (C2-C6)alkanoyl;

R2represents hydrogen, (C1-C6)-alkyl, halogen, cyano, carboxyl, nitro - or-other7group, in which R7has the values listed above;

R3represents hydrogen, (C1-C6)-alkyl or (C2-C6) alkanoyl; and their pharmaceutically acceptable salts; and in which,

(i) when at the same time, R2represents hydrogen, (C1-C6)alkyl, halogen or cyano, and R3is hydrogen, R1and n have the meanings specified above, then at least one of R4,R5and R6is other than hydrogen;

(ii) when R is linked to position 3 of the indole ring, n=0 and R3and R6each represents hydrogen or CH3then at least one of R2, R4and R5is other than hydrogen;

(iii) when R is linked to position 2 of the indole ring, n=0 and R2, R2is CH3in position 3 of the indole ring, R3is CH3and R4and R5hydrogen, then R6different from hydrogen or CH3.

In the compounds of the invention, each of the substituents R, -OR1and R2can independently be present or benzene or pyrrole part of the condensed system of rings, forming indole.

The invention includes in its scope all the possible isomers, stereoisomers, in particular the Z and E isomers and their mixtures, the metabolites and precursors or metabolites of bioresistance (otherwise known as prodrugs of compounds of formula (I).

Preferably, when the substituent R is associated with indole link in position 2 and 3, in particular in position 3.

When n is equal to 2, each of the groups-OR1may be identical with another, or different from it.

Preferably, when the Deputy OR1attached in position 4,5,6 or 7, in particular in position 5 or 7.

Preferably, when the substituent R2linked to the benzene ring, in particular in position 5.

Of course, only one of the substituents R, -OR1and R2may be associated with indole system key 4 or 5, especially in position 5.

When R4is carboxyl, the nitro-group or group-other7in which R7has set the above values, it is preferable that R2did not have the same values. On the contrary, when R2is carboxyl, the nitro-group or group-other7in which R7has set the above values, it is preferable that the substituent R4was other than the carboxyl group, the nitro-group or group-other7.

Alkyl groups and the alkyl part alkanoyl groups can be straight or branched alkyl chain. Preferably, when (C1-C6)-alkyl group is a (C1-C4)-alkyl group, for example, stands, ethyl, propylene, isopropyl, bootrom, second-bootrom or tert-bootrom, in particular, stands or ethyl. Alcoolica group (C2-C6) is preferably (C2-C4)alkanoyloxy group, in particular acetyl, propionyl or butyricum. Halogen preferably represents chlorine, bromine or fluorine, in particular bromine.

Pharmaceutically acceptable salts of the compounds of the invention include the salts formed by FORNEY acids, or with an organic acid, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, almond and salicylic acids, and salts with inorganic bases, for example, with the bases of alkali metals, especially sodium or potassium, or with bases of alkaline-earth metals, especially calcium or magnesium, or with organic bases, for example, bonds alkylamines, preferably triethylamine.

As stated above, the invention includes in its scope also the pharmaceutically acceptable bio-precursors (otherwise known as prodrugs of compounds of formula (I), i.e. compounds that have the formula, different from the above formula (I), but which, nevertheless, when introduced into the human body become directly or indirectly in vivo into a compound of formula (I). Preferred compounds of the invention are the compounds of formula (I) in which R is as defined above, R4represents a hydroxy-, amino-, nitrile carboxy-group, and R5and R6are hydrogens, R1represents hydrogen or (C1-C6)alkyl, n is zero or 1, R2presented is acceptable salt.

More preferred compounds of the invention are the compounds of formula (I), in which

R has the foregoing values, R4represents a hydroxy-, amino - or carboxy-group, R5and R6are hydrogens, n is 0 or 1; R1represents hydrogen, R2represents hydrogen, amino or carboxy group, R3is hydrogen, and their pharmaceutically acceptable salts.

Examples of typical compounds of the invention are the following compounds, which respectively can be either Z - or E-diastereoisomer, or Z, E-mixtures of the above-mentioned diastereoisomers:

5-hydroxy-3-[(3'-indolyl)methylene]-2-oxindole,

3-[(5'-carboxy-3'-indolyl)methylene]-2-oxindole,

3-[(5'-amino-3'-indolyl)methylene]-2-oxindole,

5-carboxy-3-[(3'-indolyl)methylene]-2-oxindole,

5-amino-3-[(3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(7'-hydroxy-3'-indolyl)methylene]-2-oxindole,

3-[(5',7'-deoxy-3'-indolyl)methylene]-2-oxindole,

5-amino-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-amino-3'-indolyl)methylene]-2-oxindole,

5-carboxy-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-carboxy-3'-indolyl)it]-2-oxindole,

and, where appropriate, their pharmaceutically acceptable salts.

Compounds of the invention and their pharmaceutically acceptable salts can be obtained by the method consisting in condensing the aldehyde of formula (II)

< / BR>
where R1, R2, R3and n are installed above values with the compound of the formula (III)

< / BR>
in which R4, R5and R6have the values stated above: and, if required, converting the compounds of formula (I) into another compound of formula (I), and/or, if required, converting the compounds of formula (I) and its pharmaceutically acceptable salt and/or, if required, converting a salt into a free compound, and/or, if required, in the separation of a mixture of isomers of compounds of formula (I) to separate the isomers. Each of the substituents R2, -OR1and -- CHO in the compound of formula (II) can independently be present or benzene or pyrrole part of the indole ring.

The interaction of the compounds of formula (II) with the compound of the formula (III) is a process which is similar to the processes which can be carried out in accordance with known methods, as described below, preferably in the presence of a basic catalyst, N. the ptx2">

For example, the reaction of compounds of formula (II) with the compound of the formula (III) may be carried out under the reaction conditions of Coverages, as described, for example, in G. Toncs, Organic Reactions , 204 (1967). Suitable catalyst are organic bases, such as pyridine, piperidine or diethylamine. The condensation may be carried out in an inert organic solvent, e.g. pyridine, ethanol, methanol, benzene or dioxane, at temperatures lying in the range from 0 to 100oC.

It is preferable to carry out the reaction in warm ethanol solution in the presence of piperidine as a catalyst.

The compound of formula (I) can be converted into another compound of formula (I) in accordance with known methods. For example, deesterification the compounds of formula (I), in which one or more of the substituents R1are (C1-C6-alkali, with the aim of obtaining the compounds of formula (I), in which one or more of the substituents R1are hydrogen, can be accomplished by methods well known in organic chemistry. In the case of a simple methyl ester of phenol removal can be performed, for example, tribromide boron, as described in I. F. N. Mc by omic, Tetrahedron 2289 (1968). Recommended and the PPU, containing, possibly, nitrogen or oxygen. The reaction can be carried out in an inert organic solvent such as methylene chloride, pentane or benzene, in an inert atmosphere, e.g. nitrogen, at temperatures lying in the range from -70oWith up to room temperature.

The acylation of compounds of formula (I) in which one or more-OR1and/or R4are oxypropane order to obtain the corresponding compound of formula (I), in which one or more-OR1and/or R4are (C2-C6-alkanoyloxy, can be done by interaction with a reactive derivative of a suitable carboxylic acid, such as the anhydride or calendarized, in the presence of an alkaline agent, at temperatures lying in the range from 0 to 50oC. it is Preferable to perform the acylation interaction with the appropriate anhydride in the presence of an organic base such as pyridine.

Optional receiving salts of the compounds of formula (I), as well as the conversion of a salt into a free compound and the separation of a mixture of isomers into individual isomers may be made by conventional methods.

For example, separation of a mixture of geometric and chromatography or column chromatography, or liquid chromatography high pressure.

The compounds of formula (II) can be obtained according to known methods from compounds of formula (IV)

< / BR>
For example, derivatives of 3-formylindole formula (II) can be obtained from compounds of formula (IV) method of formirovaniya N-methylformamide formula (IV) method of formirovaniya N-methylformamide and acid chloride phosphoric acid in accordance with well-known way of Vilsmeier-khaak (see review in W. G. Jackson et al. I. Am. Chem. Soc. 533). When engaged position 3, are formed derivatives of 2-formylindole.

The compounds of formula (III) and (IV) are known or can be obtained by known methods from known compounds.

Pharmacology

Compounds of the invention have a specific inhibitory effect on tyrosinekinase. Therefore, they can be useful in the treatment of cancer and other pathological conditions associated with growths, for example, for inhibiting the development of atherosclerotic plaques in mammals, including humans.

Typical therapeutic indications corresponding to the last occasion of use, are reocclusion following plasticheskiye research at the molecular level of tumor rebirth identified a family of genes appropriate plan of oncogenes, whose altered expression causes tumorigenesis. For example, RNA of oncoviruses has such oncogenic sequence whose expression defines neoplastic conversion of infected cells. Some of these onkoginekologicheskih proteins, such as RV-Src, Rgag-ges, Rgag-fpsand Rgag-fgrshow the activity of protein tyrosine kinase, i.e., they catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues in the substrate protein. In normal cells, the activity of tyrosine kinase show some receptors growth factor, for example, the receptors for PDGF, EGF, a-TGF and insulin. Binding of the growth factor (GF) activates the tyrosine kinase receptor for autophosphorylation and for phosphorylation of adjacent molecules on the tyrosine.

So, I think that the phosphorylation of these receptors tyrosine kinase plays an important role in signal transduction and that the main function of tyrosine kinase activity in normal cells is the regulation of cell growth. The perturbation of this activity of oncogenic tyrosine kinases that or preproinsulin, and/or show a modified substrate specificity, can Vinas may be useful for studying the mechanism of carcinogenesis, proliferation and cell differentiations, and it can be effective for the prevention and chemotherapy of cancer and other pathological overgrown formations.

Specific protein tyrosine kinase activity of the compounds of the invention are shown in the following experiments.

Cleaning the V-abl kinase

Use the enzyme tyrosine kinase p95v-ablAbelson (Abelson), which receive and emit as follows: 1 l of the culture of HB-130 cells in LB medium supplemented with ampicillin, and grown at 30oSince, as described in Wang et al. J. Biol. Chem. 64 (1985). The expression of v-abl-protein induce a temperature shift to 42oC for 3-4 hours, the Bacterial cells are collected on ice, centrifuged and frozen in liquid nitrogen. The cell sediment are lysed as described in Ferguson et al. J. Biol. Chem. 3652 (1985), and in Biochem J. 321 (1989). Briefly, bacterial proteins are removed by differential solubilization with doxycholate sodium, NaCl-octylglucoside at different stages. Insoluble v-abl protein solubilizer 2M KSCN, and subjected to dialysis against 100 volumes of 50 mm Tris-HCl, pH 7.5, 1 mm etc and 0.1 mm dithiothreitol (buffer A). Soluble proteins separated on anion-exchange chromatographic column Packed the Mono-Q system f.p.l.c. Activists glycerin, and keep a small aliquot at -20oC.

Check fosforilirovanija basic protein of myelin

Test in vitro the basic protein of myelin as a substrate carry out as follows: protein phosphorylation is carried out, soaking in thermostat 40 ng of purified v-abl kinase, 1,5 Ci[-32p] ATP, 10 M cold ATP, 56 M basic protein of myelin in 50 μl of 25 mm Tris-HCl, pH 8.0, containing 10 mm MgCl2, 0.1 mm of dithiothreitol (kinase buffer) at 22oC. the Reaction is stopped by adding equal volumes of buffer for electrophoresis of double concentrated Laemmli [U. K. Laemmli, Nature (London) 680 (1970). The samples are again boiled for 3 min, and separated in SDS-PAGE (15% acrylamide). The gels are dried and kept in the films for autoradiography within 15-30 min at -70oC. Strip localize autoradiography, cut out from the gel and believe in a liquid scintillation counter.

Check autophosphorylation

To check autophosphorylate, v-abl-kinase immunoassay antibodies antiphosphotyrosine, and the resulting immunocomplex analyze in 50 μl of kinase buffer in the presence of 10 μm ATP and 10Ci[-32p] -ATP. After a 15-min exposure at room temperature and the reaction stopped by boiling the La film for autoradiography up to 3 h at -70oC. Strip localize autoradiography, cut out and consider it as described above.

Below the connection representing the invention, compared with the corresponding dehydrosilybin similar to that covered by the General formula patent application WIPO 91/13055. The comparison shows that the introduction of a hydroxyl group significantly enhances the inhibitory activity through autophosphorylation, whereas the efficacy toward exogenous substrates increases only slightly.

Check phosphorylation of the basic protein of myelin, IC50(μm) (mm)

5-hydroxy-3-[(3'-indolyl)methylene]-2-oxindol 0,4

3-[(3'-indolyl)methylene]-2-oxindol 0,6

Check autophosphorylate, IC50(μm) (mm)

5-hydroxy-3-[(3'-indolyl)methylene]-2-oxindol 0,4

3-[(3'-indolyl)methylene]-2-oxindol 10

Due to their high activity and low toxicity, the compounds of the invention can be safely used in medicine. For example, we found that the acute toxicity (IC50compounds of the invention for mice, defined by a single administration of increasing doses and measured on the seventh day after the treatment, is insignificant.

Compounds of the invention can be administered in different or film, liquid solutions or suspensions, with the introduction of rectal

in the form of a suppository, parenteral administration by intramuscular or intravenous injection or infusion, or locally.

The dosage depends on age, weight, condition of the patient and the route of administration, for example, the dosage adopted for an adult, in oral introduction, can be from 10 up to 150-200 mg per dose when taking 1-5 times a day. Of course regimen of medication may be adjusted to obtain the optimum therapeutic response.

The invention includes pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt, in combination with pharmaceutically acceptable excipient (which can be a carrier or a diluent).

The aim of the invention is also the use of compounds of formula (I) as defined above, or its pharmaceutically acceptable salt for the manufacture of a medicinal product for use as an inhibitor of tyrosine kinase, in particular as anti-cancer remedies or means of preventing overgrowth (antiproliferative). Pharmaceutical compositions containing soy is

For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, glucose, sucrose, cellulose, corn or potato starch, binder, for example, silicon dioxide, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols, binding agents, e.g. starches, Arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, disaggregated substances, such as starch, alginic acid, alginates or starch glycolate, sodium, mixtures rapidly produce gases, sweeteners, wetting, such as lecithin, Polysorbate, laurilsulfate and generally non-toxic and pharmacologically inactive substances used in the formulations of medicines. Mentioned pharmaceutical preparations can be obtained in a known manner, for example by mixing, granulating, tabletting, ways, including the application of sugar and film coating. Liquid dispersion for oral administration may be, for example, syrup, emulsion or suspension.

A syrup may contain a carrier, e.g., sucrose, or Saha is eaten, as, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, stielow water, olive oil, etiloleat, glycols, e.g. propylene glycol, and, if desirable, a suitable amount of hydrochloric lidocaine.

The solutions for intravenous injections or infusions may contain devices such as, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

Suppositories can contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, surface active ester of polyoxyethylenesorbitan and fatty acids or lecithin.

Compositions for local application, for example, creams, lotions or pastes can be obtained by mixing the active ingredient with conventional oily or emulsification inert filler.

Another aim of the invention is a combined method of treatment is the introduction: 1) the compounds of formula (I), or its pharmaceutically acceptable salts, and 2) an additional anti-cancer agents, in sufficient quantity and almost together for a time sufficient to obtain a useful therapeutic effect.

The aim of the invention is also to offer products containing the compound of formula (I) or its pharmaceutically acceptable salt, and an additional anti-tumor agent as a combined preparation for simultaneous, separate or subsequent application in anticancer therapy. The term "anticancer agent" means that it covers as a single drug, and "cocktails", i.e. a mixture of such medicines, appropriate clinical practice.

Anticancer drugs, which can be part of the preparations containing the compound of the invention, or, alternatively, may be appointed by the combined method of treatment are, for example, doxorubicin, daunomycin, epirubicin, idarubitsin, etoposide, fluorouracil, mephalan, cyclophosphamide, bleomycin, vinblastine and mitomycin, or a mixture of two or more of these compounds.

Compounds of the invention may therefore be used in the treatment to reduce the intensity of the PTO, for example, glycoside anthracycline, such as doxorubicin, daunomycin, epirubicin or idarubitsin, as mentioned above, together with antiproliferative agent. The compound of the invention and an antitumor agent, such as glycoside anthracycline, can be assigned to improve the condition of the patient having leukemia, such as myeloblastic leukemia, lymphoma, sarcoma, neuroblastoma, Wilms tumor, or malignant disease of the bladder, breast, lung or thyroid.

Example 1. 5-Hydroxy-3-[(3'-indolyl)methylene]-2-oxindole [1, R as defined, n=0, R2=R3=R5=R6=H, R4=5-OH]

A solution of 3-indocarbocyanine (145 mg, 1 mmol), 5-hydroxy-2-oxindole (149 mg, 1 mmol) and piperidine (60 mg, 0.7 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60oC in nitrogen atmosphere. Then the reaction mixture is cooled and evaporated in vacuum to dryness. The residue is subjected to column chromatography on silica gel, using as eluent methylene chloride with 4% ethanol. So get a pure compound named in the heading, with 60% of the outputs (166 mg). According to another method, the reaction mixture was concentrated in vacuo and then cooled to 0-5oWith, the sediment Hotfile the program receive subsequent crystallization from ethanol.

WITH17H12N2O2contains, 79,89, N OF 4.38, N 10,14

found, WITH 73,51, N IS 4.21, N 9,92

Mass spectrum m/z: 276.

X cm-1(CVG): 3600-2500 (NH, OH), 1650 (CO), 1600, 1580, 1530, 1480 (C=C).

So pl. 293o(With Razlog.).

In accordance with the above-described method can be obtained the following compounds:

5-carboxy-3-[(3-indolyl)methylene]-2-oxindole,

5-amino-3-[(3-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

Mass spectrum m/z: 282,

X cm-1(CVG): 3600-2600 (NH, OH)- 1655 (CO), 1605, 1585, 1535 (C=C),

5-hydroxy-3-[(7'-hydroxy-3'-indolyl)methylene]-2-oxindole,

3-[(5-7'-deoxy-3'-indolyl)methylene]-2-oxindole,

5-amino-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-amino-3'-indolyl)methylene]-2-oxindole,

5-carboxy-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-hydroxy-3-[(5'-carboxy-3'-indolyl)methylene]-2-oxindole,

5-amino-3-[(7'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-carboxy-3-[(7'-hydroxy-3'-indolyl)methylene]-2-oxindole,

5-methoxy-3-[(5'-methoxy-3'-indolyl)methylene]-2-oxindole,

5-acetoxy-3-[(5'-acetoxy-3'-indolyl)methylene]-2-oxindole,

3-[(5'-carboxy-3'-indolyl)methylene]-2-oxindole,

C18H12N2O3contains, WITH 71,04, N 3,98, N OF 9.21

found 70,600-3000 (NN), 3000-2100 (OH), 1710 (WITH), 1640, 1620, 1600, 1550 (arene):

3-[(5'-amino-3'-indolyl)methylene]-2-oxindole,

WITH17H13N3O contains, 74,14, N 4,71, N 15,26

found, 73,88, N 4,51, N 14,91

Mass spectrum m/z: 275.

So pl. 250o(With Razlog.).

X cm-1(KBR): 3300, 2380 (NH), 1670 (CO), 1600, 1510 (C=C),

3-[(5'-nitro-3'-indolyl)methylene]-oxindol,

WITH17H11N3O3contains, 66,88, N 3,63, N 13,76

found, 66,58, N 3,74, N 13,64

Mass spectrum m/z: 305.

So pl. >350oWITH

X cm-1(KBR): 3350, 3230 (NH), 1680 (CO), 1620, 1605,

1580 (C=C), 1530, 1340 (NO2)

3-[(1'-methyl-3'-indolyl)methylene]-2-oxindole,

WITH18H14N2O contains, WITH unchanged at 78.81, N 5,14, N OF 10.21,

found, 78,42, N 5,17, N 10,00,

Mass spectrum m/z: 274.

So pl. 230o(With Razlog.)

X cm-1(CVG): 3300-2000 (NH), 1680 (CO), 1610, 1600, 1570, 1500 (C=C),

3-[(3'-indolyl)methylene]-1-methylene-2-oxindole,

C18H14N2O contains, WITH unchanged at 78.81, N 5,14, N OF 10.21

found, WITH 78,61, N 5,16, N 10,23,

Mass spectrum m/z: 274.

So pl. 274oWITH

X cm-1(KBR): 3220 (NH), 1676 (CO), 1605, 1500, 1490 (C=C).

Example 2. 5-Hydroxy-3-[(5'-hydroxy-3-indolyl)methylene]-2-oxindol

[1, R is set higher the value, n=1, R1=R2=R3=R5=R6

To a stirred solution of 5-methoxy-3-[(5'-methoxy-3'-indolyl)methylene] -2-oxindole (310 mg, 1 mmol) in anhydrous dichloromethane (10 ml) at -78oC, in an atmosphere of nitrogen for 10 minutes, add 1.0 M solution trichromate boron in dichloromethane (3 ml, 3 mmol). The resulting mixture is stirred for another 1 h at -78oWith, and then allow to warm to room temperature. After stirring for 1.5 h at 20-25oThe mixture is cooled to -10oC and then quenched by adding dropwise water 910 ml) for 10 minutes After addition of ethyl acetate the organic layer was separated, washed with water, dried over Na2SO4and evaporated in vacuum to dryness. The residue is crystallized from ethanol, and receive, thus, 198 mg of pure compound named in the title (yield 70%).

WITH17H12N2O3contains, 72,33, N 4,29, N 6,38

found, 71,22, N 4,07, N 6,29

Mass spectrum m/z: 282.

X cm-1(CVG): 3600-2600 (NH, OH), 1655 (CO), 1605, 1585, 1535 (C=C).

In accordance with the above procedure and taking over the starting compound corresponding simple methyl esters, can be obtained hydroxyl soy is [1, R is set higher the value, n=1, R1=AC, R4=5-0 AC, R2=R3= R5=R6=H]

The source material for acylation in this example is 5-hydroxy-3-[(5'-hydroxy-3'-indolyl)methylene]-2-oxindole, which can be obtained in accordance with the procedures described in examples 1 and 2.

To a chilled solution of 5-hydroxy-3-[(5'-hydroxy-3'-indolyl) methylene]-2-oxindole (282 mg, 1 mmol) in dry pyridine (0.5 ml) is added acetic anhydride (306 mg, 3 mmol), the mixture was kept at 0-5 oWith during the night. After that, the mixture was concentrated in vacuo, the residue is dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from a mixture of chloroform-methanol, and get a pure compound named in the heading, with 80% yield (301 mg).

WITH21H16N2H5contains, WITH 67,02, N 4,29, N 7,44

found, 66,91, N OF 4.05, N 7,29

Mass spectrum m/z: 376.

X cm-1(CVG): 3600-3200 (NH), 1750 (OH)3SOO), 1650 (ONH), 1600, 1580, 1530 (C=C).

In accordance with the procedure described above, hydroxyl compounds, obtaining in examples 1 and 2, can be converted into the corresponding (C2-C6)-alcoholattributable (176 mg, 1.3 mmol) and acid chloride phosphoric acid (199 mg, 1.3 mmol) is stirred for 15 min at 20 25oIn nitrogen atmosphere, then add a solution of 5-nitroindole (162 mg, 1 mmol) in 1,2-dichloroethane (5 ml) and the mixture is heated at boiling temperature under reflux for 3 hours After cooling, the mixture was poured into ice water, the precipitate is filtered off and washed with water. After that, the rest chromatographic on silica gel, using as eluent benzo/l

WITH9H6N2O3contains, 56,85, N 3,18, N 14,73

found, 56,79, N 3,01, N 14,51

Mass spectrum m/z: 190.

X cm-1(KBR): 3140, 3090 (NH), 1650 (CO), 1511, 1345 (NO2)

These intermediate nitro compounds, except that they lead to the final products of the formula (I) with R2=NO2may also give rise to the final products with the group R2=NH2that may be obtained from the first recovery.

Similarly, you can obtain the following compounds containing a protective group, which, after removal of the protective group at an appropriate stage of the synthesis, also result in a product of formula (I) with a free carboxyl (R2=COOH) and a free hydroxyl group (R2=OH) COO the e pills, each of which weighs 0,150 g and contains 25 mg of active connections:

Ingredients (for 10,000 tablets):

5-hydroxy-3-[(3'-indolyl)methylene]-2-oxindol 250 g

lactose 800 g

corn starch 415 g

the talcum powder 30 grams

magnesium stearate 5 g

Mix 5-hydroxy-3-[(3'-indolyl)methylene]-2-oxindole, the lactose and half the corn starch, the mixture is then sieved through a sieve with openings of 0.5 mm Corn starch (10 g) suspendered in warm water (90 ml), the resulting paste is used for granulation of powder. The granulate is dried, crushed into a sieve with a pore size of 1.4 mm, then add the remaining quantity of starch, talc and magnesium stearate are thoroughly mixed and processed into tablets.

Example 6. Prepare capsules, each of which contains a dose 0,200 g, including 20 mg of active substance.

Composition for 500 capsules:

3-[(5'-amino-3'-indolyl)methylene]-2-oxindol 10 grams

lactose 80 g

corn starch 5 grams

magnesium stearate 5 g

This formulation encapsulates in hard gelatin capsules consisting of two parts, and depending on 0,200 g in each capsule.

1. Derivatives methylisoxazole General formula

< / BR>
where R represents a group

< / BR>
gdppw or group other7in which R7is hydrogen or C1< / BR>
WITH6-alkyl;

R5is hydrogen, (C1WITH6)-alkyl or halogen;

R6is hydrogen or C1WITH6-alkyl;

n is 0,1 or 2;

R1hydrogen, C1WITH6-alkyl or C2- C6-alkanoyl;

R2hydrogen, C1WITH6-alkyl, halogen, cyano, carboxy, nitro-group or other group7in which R7has the above meanings;

R3hydrogen, C1WITH6-alkyl or C2- C6-alkanoyl,

moreover, in the case when R2hydrogen, C1WITH6-alkyl, halogen or cyano, then R3hydrogen, R and n are as defined above values and at least one of the substituents R4, R5and R6is other than hydrogen; when R is attached in position 3 of the indole ring, n is 0 and R3and R6each represents hydrogen or CH3then at least one of R2, R4and R5is other than hydrogen; when R is attached in position 2 of the indole ring, n is 0 and R2, R3, R4and R5each represents hydrogen, then R6different from methyl, and when R is attached to the floor
represent hydrogen, then R6different from hydrogen or methyl,

and its pharmaceutically acceptable salts.

2. Connection on p. 1, in which R has the meanings given in paragraph 1, R4represents a hydroxy, amino, nitro - or carboxypropyl, and R5and R6are hydrogen, R1represents hydrogen or C1WITH6-alkyl, n0 or 1, R2represents hydrogen, carboxy, amino or nitro-group, R3represents hydrogen, or its pharmaceutically acceptable salt.

3. Connection on p. 1, in which R has the meanings given in paragraph 1, R4represents a hydroxy-, amino - or carboxypropyl, R5and R6represents hydrogen, n is 0 or 1, R1hydrogen, R2represents hydrogen, amino or carboxypropyl, R3is hydrogen, and its pharmaceutically acceptable salts.

4. A compound selected from the group of 5-hydroxy-3-[(3'-indolyl) methylene] -2-oxindole, 3-[(5'-carboxy-3'-indolyl)methylene]-2-oxindole, 3-[(5'-amino-3'-indolyl)methylene] -2-oxindole, 5-carboxy-3-[(3'-indolyl)methylene]-2-oxindole, 5-amino-3-[(3'-indolyl)the methylene]-2-oxindole, 5-hydroxy-3-[(5'-hydroxy - 3'-indolyl)methylene] -2 - oxindole, 5-hydroxy-3-[(7'-hydroxy-3'-ind is len]-2-oxindole, 5-carboxy-3-[(5'-hydroxy-3 indolyl) methylene]-2-oxindole, 5-hydroxy-3-[(5'-carboxy - 3'-indolyl)methylene] -2-oxindole, 5-amino-3[(7'-hydroxy-3'-indolyl) methylene]-2-oxindole, 5-carboxy-3-[(7'-hydroxy -3'-indolyl) methylene]-2-oxindole, 5-methoxy-3-[(5'-methoxy-3'-indolyl)methylene]-2 - oxindole, 5-acetoxy-3-[(5'-acetoxy - 3'-indolyl) methylene]-2-oxindole, 3-[(5'-carboxy-3'-indolyl)methylene] -2-oxindole, 3-[(5'-amino-3'-indolyl) methylene]-2-oxindole, 3-[(5'-nitro-3'-indolyl)methylene]-2-oxindole, or their pharmaceutically acceptable salts.

5. The method of obtaining the compounds of formula I, or its pharmaceutically acceptable salts, characterized in that exercise the concentration of the aldehyde of General formula II

< / BR>
where R1, R2, R3and n have the meanings given in paragraph 1,

with a compound of General formula III

< / BR>
where R4, R5and R6have the meanings given in paragraph 1,

followed if necessary by a simple diesterification obtained product, where one or more of the groups-OR1represents a C1WITH6-alkoxy, obtaining the compounds of formula I where one or more of the groups OR1hydroxy, and/or subsequent acylation of the resulting product, where one or more of the groups OR1and/or Rhydroxy.

6. Pharmaceutical composition having inhibitory to tyrosinekinase activity containing the active substance and a pharmaceutically acceptable excipient, wherein the active substance contains a compound of formula I under item 1 or its pharmaceutically acceptable salt in an effective amount.

7. The pharmaceutical composition according to p. 6, characterized in that it contains as active substance a compound selected from 3-[(1'-methyl-3' -indolyl]-2-oxindole, 3-[(3'-indolyl) methylene]-1-metil-2-oxindole and their pharmaceutically acceptable salts.

8. The compound or its salt under item 1 with the inhibitory tyrosinekinase activity.

9. The compound or its salt under item 1, with antiproliferative activity.

10. The compound or its salt under item 1, have anticancer activity or activity in the treatment of coronary artery disease.

 

Same patents:

The invention relates to a method for 2,4,6,8-tetraazabicyclo[ 3.3.0] octane-3,7-dione (glycoluril), which is an intermediate for the synthesis of disinfectant, bleaching detergents [1] activators bleaching products [2,3] explosives [4] antioxidants [5]

A method of obtaining 7,8-diphenylpyrrole the interaction of aromatic diketone of benzil with urea in formic acid at boiling with output derived glycoluril 80% [6]

The disadvantage of this method of production is the inability of the synthesis target glycoluril in the above conditions with satisfactory output

The invention relates to medicine, namely to pharmacology and medicinal, with interferonogenna and immunomodulatory effects

The invention relates to medicine, namely to obstetrics

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: agent comprises glucosamine salt as saccharide, dimethylsulfoxide, ointment base and ibuprofen or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen as a nonsteroid anti-inflammatory agent. Glucosamine hydrochloride, glucosamine sulfate sodium, potassium or calcium salt is used as glucosamine, and diclofenac potassium or sodium salt is used as diclofenac salt. New ointment shows high perfusion rate of active substances to the articulation zone and enhanced effectiveness. Invention expands assortment of agents used in treatment of articulations.

EFFECT: improved, enhanced and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: invention relates to agents of topical applying used in treatment of articulation diseases. Proposed agent comprises mixture of chondroitin sulfate and glucosamine salts as a saccharide, the compound taken among the group nonsteroid anti-inflammatory agents, in particular, ibuprofen or nimesulid, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen, dimethylsulfoxide and an ointment base taken in the definite ratio of components. Invention provides enhancing effectiveness due to the content a mixture of low-molecular and high-molecular saccharides in it that results to increasing diffusion rate of active component to the articulation zone and also the compound taken among the group of nonsteroid anti-inflammatory agents. The combined using these agents provides the curative synergetic effect.

EFFECT: improved and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

FIELD: medicine, neurooncology.

SUBSTANCE: one should carry out chemotherapy and irradiation till radical dosage. Moreover, 2-3 d before the onset of radiation therapy and during the whole course of irradiation one should indicate the intake of indometacin at daily dosage being 300 mg, and 8-14 d before the end of therapy course or the stage of radiation therapy it is necessary to conduct chemotherapeutic cycle with vincristine at total dosage being 4 mG and lomustine at total dosage 160-240 mg. At performing a split course of irradiation the intake of indometacin should be indicated between the stages. The innovation enables to increase radio sensitivity of malignant tumor, suppress angiogenesis, proliferative activity and increased cytotoxic activity of chemopreparations.

EFFECT: higher efficiency of therapy.

1 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves intragastrically introducing indometacin to rats at a dose of 4.5-5 mg/kg of mass after holding the animals without food and water during 5 days.

EFFECT: enhanced effectiveness of bleeding and perforating ulcer formation.

2 tbl

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to composition possessing an anti-inflammatory effect and useful for oral administration in form of emulsion preliminary concentrate. Composition comprises NO-releasing nonsteroid anti-inflammatory drug, surface-active substance, oil or semisolid fat and forms in situ emulsion of type oil-in-water after contact with aqueous medium, such as gastroenteric fluid. Also, invention relates to a medicinal formulation based on thereof, oral emulsion, set based on thereof and a method for treatment of inflammation and pain. Proposed compositions possess the improved availability.

EFFECT: improved and valuable properties of composition.

40 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.

EFFECT: improved preparing method, improved pharmaceutical properties of composition.

30 cl, 12 tbl, 28 ex

FIELD: organic chemistry, medicine, pharmaceutical chemistry.

SUBSTANCE: invention relates to new compound - 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole mesylate and its hydrates. Indicated mesylate salt exceeds other 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole salts by its antiviral activity and can be used in different medicinal formulations. Invention expands assortment of agents used for treatment of viral infection. New antiviral agent shows high effectiveness treatment and low toxicity.

EFFECT: enhanced and valuable medicinal properties of agent and composition.

3 cl, 6 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of novel intermediate indoline compounds of the general formula (VIII): wherein R1 means (C1-C20)-alkylcarbonyl; R2 and R3 are similar or different and each means a lower alkyl group; R4 means hydrogen atom (H), (C1-C4)-alkyl or its salts. Method involves addition of pivaloyl group to compound of the general formula (VII): wherein R1, R2, R3 and R4 are given above, or its salt.

EFFECT: improved method of synthesis.

2 cl, 24 ex

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